Abstract
BackgroundDNA methylation is an epigenetic mark that balances plasticity with stability. While DNA methylation exhibits tissue specificity, it can also vary with age and potentially environmental exposures. In studies of DNA methylation, samples from specific tissues, especially brain, are frequently limited and so surrogate tissues are often used. As yet, we do not fully understand how DNA methylation profiles of these surrogate tissues relate to the profiles of the central tissue of interest.ResultsWe have adapted principal component analysis to analyze data from the Illumina 450K Human Methylation array using a set of 17 individuals with 3 brain regions and whole blood. All of the top five principal components in our analysis were associated with a variable of interest: principal component 1 (PC1) differentiated brain from blood, PCs 2 and 3 were representative of tissue composition within brain and blood, respectively, and PCs 4 and 5 were associated with age of the individual (PC4 in brain and PC5 in both brain and blood). We validated our age-related PCs in four independent sample sets, including additional brain and blood samples and liver and buccal cells. Gene ontology analysis of all five PCs showed enrichment for processes that inform on the functions of each PC.ConclusionsPrincipal component analysis (PCA) allows simultaneous and independent analysis of tissue composition and other phenotypes of interest. We discovered an epigenetic signature of age that is not associated with cell type composition and required no correction for cellular heterogeneity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0011-y) contains supplementary material, which is available to authorized users.
Highlights
DNA methylation is an epigenetic mark that balances plasticity with stability
It is important to note that this technique, as currently applied, does not distinguish between DNA methylation and DNA hydroxymethylation, so our reports of DNA methylation in brain are a composite of both marks
Variability of DNA methylation between brain and blood was moderately concordant Having identified biological variables that were correlated with nearly 85% of the variability in our DNA methylation data, we addressed the degree to which methylation varied across individuals, and whether this variability was consistent across tissues
Summary
DNA methylation is an epigenetic mark that balances plasticity with stability. In studies of DNA methylation, samples from specific tissues, especially brain, are frequently limited and so surrogate tissues are often used. CpG density is commonly classed into four categories: high-density CpG island (HC), intermediate density CpG island (IC), intermediate density island shore (ICshore, meaning intermediate density regions found flanking HC regions), and low-density CpG island (LC) [2,3] This CpG density is related to both DNA methylation level and variability [1,2]. While the common form of DNA methylation described above has been the most extensively studied, many other related modifications have recently emerged. Chief among them is 5hydroxymethylcytosine, which exists as the oxidized form of the canonical 5-methylcytosine mark of DNA methylation. Most sodium bisulfite-based methods of measurement of DNA methylation cannot distinguish between the different kinds of modifications
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